Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels.

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5-C-phosphate-G-3 (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = -2.69, p = 0.05) and fat distribution (β = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = -0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood

HIV-1 VPR impairs cell growth through the inactivation of two genetically distinct host cell proteins

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The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses.: The HERV family MSRV retrovirus activates innate immunity

rendre public SVPInternational audienceMultiple sclerosis-associated retroviral element (MSRV) is a retroviral element, the sequence of which served to define the W family of human endogenous retroviruses. MSRV viral particles display proinflammatory activities both in vitro in human mononuclear cell cultures and in vivo in a humanized SCID mice model. To understand the molecular basis of such properties, we have investigated the inflammatory potential of the surface unit of the MSRV envelope protein (ENV-SU), the fraction that is poised to naturally interact with host cells. We report in this study that MSRV ENV-SU induces, in a specific manner, human monocytes to produce major proinflammatory cytokines through engagement of CD14 and TLR4, which are pattern recognition receptors of primary importance in innate immunity. ENV-SU could also trigger a maturation process in human dendritic cells. Finally, ENV-SU endowed dendritic cells with the capacity to support a Th1-like type of Th cell differentiation. The data are discussed in the context of immune responses and chronic proinflammatory disorders

Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4.

The MSRV (multiple sclerosis-associated retrovirus) belongs to the human endogenous retrovirus HERV-W family. The envelope protein originating from the MSRV has been found in most patients with multiple sclerosis (MS). This protein (Env-ms) has pro-inflammatory properties for several types of immune cells and could therefore play a role in MS pathogenesis by promoting the leukocyte diapedesis observed in the central nervous system of patients. Our study aims to analyze the effects of Env-ms on the blood-brain barrier (BBB) at a molecular and functional level. We demonstrate that the recombinant MSRV envelope is able to stimulate several inflammatory parameters in a human BBB in vitro model, the HCMEC/D3 brain endothelial cell line. Indeed, Env-ms induces over-expression of ICAM-1, a major mediator of leukocyte adhesion to endothelial cells, in a dose-dependent manner as well as a strong dose-dependent production of the pro-inflammatory cytokines IL-6 and IL-8. Furthermore, using a silencing approach with siRNAs, we show that Env-ms is recognized via the Toll-like receptor 4 receptor, a pattern recognition receptor of innate immunity present on endothelial cells. We also show, using functional assays, that treatment of brain endothelial cells with Env-ms significantly stimulated the adhesion and the transmigration of activated immune cells through a monolayer of endothelial cells. These findings support the hypothesis that MSRV could be involved in the pathogenesis of MS disease or at least in maintenance of inflammatory conditions, thus fueling the auto-immune disorder. MSRV could also play a role in other chronic inflammatory diseases

The envelope of human endogenous retrovirus in neuro-inflammation

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Maternal lipid profile differs by gestational diabetes physiologic subtype

Aim To characterize lipid profiles in women with different gestational diabetes mellitus (GDM) physiologic subtypes. Methods We measured seven lipid markers (total cholesterol, LDL, HDL, triglycerides, non-esterified fatty acids (NEFA), ApoA, ApoB) in fasting plasma collected in a prospective cohort of 805 pregnant women during second trimester. We estimated insulin sensitivity and secretion using oral glucose tolerance test-based validated indices. We categorized GDM physiologic subtypes by insulin sensitivity and secretion defects defined as values below the 25th percentile among women with normal glucose tolerance (NGT), as previously established. We compared lipid markers across NGT and GDM subtypes. We explored associations between lipid markers and newborn anthropometry in the overall group and stratified by glucose tolerance status. Results Among 805 women, 67 (8.3%) developed GDM. Women with GDM had higher body mass index (BMI; 29.3 vs. 26.6 kg/m2), while ethnicity (97.3% vs. 97.0% European ancestry) and age (28 vs. 29 years) were similar. In comparison to women with NGT, women with GDM characterized by a predominant insulin sensitivity defect had significantly higher triglycerides (2.20 vs. 1.82, P = 0.002), lower HDL (1.64 vs. 1.90, P = 0.01) and higher NEFA (0.34 vs. 0.24, P < 0.0001). GDM women with a predominant insulin secretion defect differed from women with NGT with respect to NEFA (0.32 vs. 0.24, P = 0.003) while other lipid markers were similar. These associations remained significant after adjusting for maternal age and BMI. Greater maternal levels of NEFA were associated with higher birth weight z-scores in women with an insulin secretion defect (BMI-adjusted r = 0.58, P = 0.01). We did not find significant associations between other lipid markers and newborn anthropometry in other groups. Conclusion Women with GDM have distinct lipid profiles based on their GDM physiologic subtype which may not be apparent when investigating GDM as a single group

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement

The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases

High performance aluminum–cerium alloys for high-temperature applications

Light-weight high-temperature alloys are important to the transportation industry where weight, cost, and operating temperature are major factors in the design of energy efficient vehicles. Aluminum alloys fill this gap economically but lack high-temperature mechanical performance. Alloying aluminum with cerium creates a highly castable alloy, compatible with traditional aluminum alloy additions, that exhibits dramatically improved high-temperature performance. These compositions display a room temperature ultimate tensile strength of 400 MPa and yield strength of 320 MPa, with 80% mechanical property retention at 240 °C. A mechanism is identified that addresses the mechanical property stability of the Al-alloys to at least 300 °C and their microstructural stability to above 500 °C which may enable applications without the need for heat treatment. Finally, neutron diffraction under load provides insight into the unusual mechanisms driving the mechanical strength

Higher maternal leptin levels at second trimester are associated with subsequent greater gestational weight gain in late pregnancy

Background: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). Methods: This prospective cohort study included 675 pregnant women followed from 1st trimester until delivery. We collected anthropometric measurements, blood samples at 1st and 2nd trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1st trimester: BMI < 25 kg/m2 = normal weight; 25 ≤ BMI < 30 kg/m2 = overweight; and BMI ≥ 30 kg/m2 = obese. Results: Women gained a mean of 6.7 ± 3.0 kg between 1st and 2nd trimester (mid pregnancy GWG) and 5.6 ± 2.5 kg between 2nd and the end of 3rd trimester (late pregnancy GWG). Higher 1st trimester leptin levels were associated with lower mid pregnancy GWG, but the association was no longer significant after adjusting for % body fat (%BF; β = 0.38 kg per log-leptin; SE = 0.52; P = 0.46). Higher 2nd trimester leptin levels were associated with greater late pregnancy GWG and this association remained significant after adjustment for BMI (β = 2.35; SE = 0.41; P < 0.0001) or %BF (β = 2.01; SE = 0.42; P < 0.0001). In BMI stratified analyses, higher 2nd trimester leptin levels were associated with greater late pregnancy GWG in normal weight women (β = 1.33; SE = 0.42; P = 0.002), and this association was stronger in overweight women (β = 2.85; SE = 0.94; P = 0.003 – P for interaction = 0.05). Conclusions: Our results suggest that leptin may regulate weight gain differentially at 1st versus 2nd trimester of pregnancy: at 2nd trimester, higher leptin levels were associated with greater subsequent weight gain – the opposite of its physiologic regulation in non-pregnancy – and this association was stronger in overweight women. We suspect the existence of a feed-forward signal from leptin in second half of pregnancy, stimulating a positive energy balance and leading to greater weight gain. Electronic supplementary material The online version of this article (doi:10.1186/s12884-016-0842-y) contains supplementary material, which is available to authorized users